Method for the nitration of phenolic compounds

ABSTRACT

A method for the regioselective ortho-directed nitration of phenolic compounds useful for the preparation of ortho-nitro-phenols according to formula (I) is described.

This invention relates to a method for the nitration of phenoliccompounds, which are useful for the preparation of ortho-nitro-phenols.

The nitration of aromatic compounds via electrophilic aromaticsubstitution is a fundamental organic reaction which has been describedand reviewed extensively in the chemical literature (Olah, G. A. et al.,Nitration: Methods and Mechanisms, VCH, New York, 1989 and Taylor, R.,Electrophilic Aromatic Substitution, J. Wiley & Sons, Chichester, 1990).Somewhat surprisingly however, despite this wealth of information, mostcommercially important industrial processes still employ ‘classical’technology requiring mixtures of nitric and sulphuric acid. The use ofsuch corrosive reagents (usually in excess) creates seriousenvironmental issues and the treatment and disposal of ‘used’ acids isexpensive. Pertinent aspects from the viewpoint of chemistry areproblems associated with over-nitration and the formation of unwantedoxidised by-products, which are often difficult to remove from thewanted product. Additionally, another serious issue with the nitrationof aromatic compounds concerns the product distribution in terms of theortho:meta:para isomer ratio (i.e. regioselectivity). It is desirablefor an industrial nitration process to display a good degree ofregioselectivity in this respect where regioisomer formation is possibleand it is commonly the case that the para-nitro isomers in particularare the commercial products of interest. This regioselectivity isdetermined by steric factors and/or electronic and solvent effects. Thenitration of, for example, an aromatic ring containing say, anelectron-donating substituent (-alkyl, —OH, —O-alkyl etc.) normallygives rise to a mixture of predominantly ortho- and para-nitratedproducts, usually following a statistical distribution. Steric bulk ofthe nitrating reagent and/or of substituents on the aromatic ring tendsto favour formation of the para-product. In many cases, the use ofsupported reagents and catalysts can also be employed to influence morefavourably the formation of the para-isomer (Smith, K., Solid Supportsand Catalysts in Organic Synthesis; Ellis Horwood: Chichester, 1992).

Logically therefore, the nitration of aromatic phenolic (Ar—OH)compounds without substituents other than hydrogen at the para-positionpresents particular problems where the formation of ortho- andpara-products is possible due to the strongly activating effect of theelectron-donating hydroxy group (where para-substituents are present,e.g. alkyl, the para-position is not available to undergo electrophilicaromatic substitution and in such cases, only ortho-nitrated productsare obtained). The use of strong mixtures of acids usually gives rise todeeply-coloured and complex reaction mixtures due to oxidativedegradation of the substrate. Nitration of phenol itself can be easilyachieved under milder conditions using dilute nitric acid in chlorinatedsolvent in reasonable combined yield (61%) with a 1:2.3 ratio ofortho:para-nitrophenol isomers (Vollhardt, K. P. C. and Schore, N. E.,Organic Chemistry, 2^(nd) ed; W. H. Freeman, New York, 1994). Nitrationusing sodium nitrate in sulphuric acid gives also a 61% combined yieldwith a ratio of 1.4:1 of ortho:para isomers (Vogel, A. I., Vogel'sTextbook of Practical Organic Chemistry, 5^(th) ed; J. Wiley & Sons, NewYork, 1989). Recently, a three-step para-selective nitration of phenolderivatives was claimed (Kanno, H. et al., DE 19723214 A1) and otherpara-selective nitrating reagents have been reported including novelmetallic nitrate dinitrogen tetroxide complexes (Firouzabadi, H. et al.,Synth. Commun., 27(19), 3301–3311 (1997); Iranpoor, N. et al., Synth.Commun., 28(15), 2773–2781 (1998)), metal nitrates under non-aqueous andaprotic conditions (Firouzabadi, H. et al., Iran. J. Chem., 16(2), 48–58(1997)) and ionic complexes of dinitrogen tetroxide with 18-crown-6(Iranpoor, N. et al., Synth. Commun., 29(19), 3295–3302 (1999)).

Not surprisingly, far fewer methods have been described for theselective ortho-nitration of para-unsubstituted phenolic compounds.Lanthanide (III) nitrate salts in refluxing ethyl acetate was reportedfor the selective meta-directed nitration of 3-substituted phenols (Gu,S. et al., Synth. Commun., 27(16), 2793–2797 (1997)) but theselanthanide reagents are prohibitively expensive and the reaction itselfevolves fumes of toxic nitrogen dioxide gas.

The selective ortho-directed nitration of a few phenolic compounds hasreceived some aftention due to the potential usefulness of the products.A two-step procedure for the selective ortho-directed nitration of3-methoxyphenol involving nitrosation followed by oxidation to give2-nitro-5-methoxyphenol has been described (Maleski, R. J., Synth.Commun., 23(3), 343–348 (1993)) although the overall yield wasrelatively low and the regioselectivity of nitrosation was undoubtedlyenhanced in this particular case by the presence of the stronglyortho/para-directing methoxy group (due to steric reasons, thepara-position relative to the methoxy group would be favoured in thiscase). A single-step nitration methodology would of course be preferableto a multi-step approach. The so-called ‘chaperon’ effect (Strazzoloni,P. et al., Bull. Chem. Soc. Jpn., 68(4), 1155–61(1995)) described forthe selective ortho-directed nitration of alkylbenzenes could not bedirectly used for oxidation-sensitive phenolic compounds (Strazzoloni,P. et al., J. Org. Chem., 63(4), 952–958 (1998)). A near selectiveortho-nitration of phenol using a microemulsion solution in the presenceof dilute nitric acid was claimed (Chhatre, A. S. et al., J. ColloidInterface Sci., 158(1), 183–187 (1993)) but the method has obviousdisadvantages for general and larger-scale preparative purposes. Veryhigh selectivity was also observed with nitronium tetrafluoroborate anda surfactant in acetonitrile (Pervez, H. et al., Tetrahedron, 44, 4555(1988)) but these conditions and reagents are again inconvenient forlarger-scale nitrations.

Somewhat more interesting is the nitration of phenol using ‘claycop’,essentially clay supported cupric nitrate which is reported to afford a92% yield of ortho-nitrophenol (Gigante, B. et al., J. Org. Chem., 60,3445–3447 (1995)). Although highly ortho-selective (13:1, ortho:para)and high-yielding, the ‘claycop’ reagent is not readily available fromcommercial sources and is also very expensive. Preparation of thereagent is tedious, the loading (mmol reagent per gram of clay support)is low and it should be stored for only short times and at lowtemperature (˜4° C.). Additionally it is presumed that the actualnitrating reagent itself is in fact in situ formed acetyl nitrate(CH₃CO—ONO₂), a known and potentially explosive compound not normallyisolated. These nitration reactions are rather exothermic with uncertaininduction periods and when using larger quantities, sometimes violentwith strong evolution of red-brown gas. Strict safety measures must beapplied when using such compounds, which due to their hazardous natureare not amenable to larger-scale preparations. A later publicationdescribed the nitration of phenol using acyl nitrates adsorbed on silicagel (Rodrigues, J. A. R. et al., Tetrahedron, 55, 6733–6738 (1999))which was claimed to improve stability of the nitrating reagent.Although almost identical selectivity and yield was obtained as for theaforementioned ‘claycop’ procedure, it does not avoid the inconvenient,expensive and dangerous preparation of the acyl nitrates and requiressubsequent adsorption onto silica gel. Due to the hazardous nature ofthese materials it would be dangerous to attempt the reaction above the50mmol scale as indicated by the authors. Notably, although the reagentworked extremely well for phenol itself, the ortho-selectivity whenapplied to other phenolic compounds was considerably lower (e.g. forisovanillin, 0.6:1, ortho:para) indicating that the method is notuniversally regioselective. Another example of the nitration ofisovanillin using 70% nitric acid in cold acetone (Napoletano, M. etal., WO 99/32449, PCT/EP98/08292) was claimed to give a 74% combinedyield of nitrated isomers with only slightly improved selectivity forthe ortho-nitrated product (ortho:para, 1.5:1) which was not thereafterisolated in pure form.

The utility of alkyl nitrates as potentially useful reagents for theselective ortho-directed nitration of para-un/substituted phenoliccompounds has not been described in the chemical literature. Onenon-related report describes the combination of n-butyl nitrate and anunusual acid catalyst (Nafion-H) for the nitration of alkylbenzenesonly, with clear preference for formation of the less-hinderedpara-nitrated product over the ortho-nitrated isomer (Olah, G. et al.,J. Org. Chem., 43(24), 4628–4630 (1978)). Other drawbacks include therelatively low stability of the particular alkyl nitrate used and theuse of a very expensive catalyst. The use of methyl nitrate for asimilar reaction described earlier (Olah, G. et al., Synthesis, 488(1973)) would be highly undesirable due to the potentially explosivenature of methyl nitrate. A Chinese group recently claimed a similarnitration of some alkylbenzenes using a different catalyst (zeoliteHZSM-5) but again the selectivity was enhanced for the para-position(Peng, X. et al., Nanjing Ligong Daxue Xuebao, 23(6), 539–541 (1999)).

U.S. Pat. No. 3,694,513 relates to a method for nitrating alkylphenolswith nitric acid in the presence of a secondary or tertiary alcohol, asecondary alkyl nitrate, an aldehyde or a ketone.

There is lacking therefore in the prior art, a safe, economical,scaleable and generally applicable nitration methodology that may beused for the high-yielding and regioselective ortho-directed nitrationof phenolic compounds especially where the formation of mixtures ofisomeric nitro-products and/or formation of oxidised by-products ispossible.

It is an object of the invention to provide a useful, high-yielding andgenerally applicable method for the regioselective ortho-directednitration of phenolic compounds. A further object of the invention is toprovide a method which avoids the disadvantages of the prior art.

Such compounds are particularly useful as pharmaceutically effectivecompounds, or precursors or intermediates in the manufacture thereof.For instance such compounds may be used in the manufacture ofcatechol-O-methyl transferase (COMT) inhibitors, which are used in thetreatment of central and peripheral nervous system disorders, such asParkinson's disease.

According to one aspect of the invention there is provided a method forthe preparation of compounds of formula I

wherein: the terms R′ and R″ may be the same or different and represent:hydrogen; lower alkyl; hydroxy; lower alkoxy; halogen; the group —CO—R¹,wherein R¹ signifies hydrogen, hydroxy, alkylaryl, alkylheterocycloalkylor optionally substituted saturated or partially unsaturated lower alkylor aryl group, or R¹ signifies the group —O—R², wherein R² signifies alower alkyl or aryl group; the group —C═N—R^(a), wherein R^(a) signifiesNHR^(a), wherein R^(a) represents optionally substituted lower alkyl oraryl group, or OR^(b) group, where R^(b) signifies hydrogen, lower alkylor lower alkanoyl; the group —C—R^(c)R^(d), where R^(c) signifies anoptionally substituted alkylidene, where R^(d) represents OR^(e) groupwhere R^(e) signifies optionally substituted lower alkanoyl or arylgroup; or R′ and R″ taken together signify an optionally substututedsaturated or partially unsaturated carbocyclic ring; m and n areindependently 0, 1 or 2; the term lower alkyl means a carbon chain,straight or branched, containing from one to six carbon atoms; the termhalogen means fluorine, chlorine, bromine or iodine; the termheterocycloalkyl means a five or six-membered cyclic ring incorporatingone or two atoms of oxygen, sulphur or nitrogen; the term aryl means aphenyl or naphthyl group optionally substituted by alkoxy, halo or nitrogroups; said method comprising reacting a phenolic compound of formulaII:

wherein the terms R′ and R″, m and n are defined above, with an alkylnitrate of formula (III)R³—ONO₂  FORMULA IIIwhere R³ represents an alkyl group straight or branched, containingpreferably from one to sixteen carbon atoms, or R³ represents acycloalkyl group containing either five or six carbon atoms.

The reaction is preferably carried out in the presence of an acidcatalyst in a substantially inert solvent.

Preferred alkyl nitrates include isopropyl nitrate, isoamyl nitrate andisooctyl nitrate (2-ethylhexyl nitrate). Compounds of formula (III) areknown and many are commercially available, or they can be made by thoseskilled in the art (e.g. Olah, G. et al., Synthesis, (2), 207–2081993)). The nitration reaction may be carried out by stirring thephenolic compound of formula II with usually an excess of the preferredalkyl nitrate (1.2–2.5 molar equivalents) in inert solvents such ashydrocarbons, chlorinated alkanes, ethers or aprotic dipolar solvents,or the reaction can be run in a mixture of the above mentioned solvents.The reaction is run with the use of mineral or organic acid catalystssuch as, for example, sulphuric acid (concentration 20–96%),hydrochloric acid, phosphoric acid, formic acid or trifluoroacetic acid,neat, or if preferred, adsorbed onto inert supports such as for example,silica gel. Alternatively a Lewis acid may be used, such as for example,boron trifluoride etherate. If desired, the reaction may be run using aphase-transfer co-catalyst such as a tetraalkylammonium halide orhydrogensulphate salt (1–5 mol%). The reaction may be performed atvarious temperatures and pressures e.g. between 0° C. and the boilingtemperature of the reaction mixture at the pressure used. The reactionproduct/s may be simply isolated after washing the reaction mixture withwater and evaporation of the reaction solvent. If necessary, separationof the major ortho-nitrated product from any minor nitro-isomercontaminants or by-products present in the crude product can be rapidlyachieved by distillation or chromatography on a suitable stationaryphase such as silica gel or alumina, using an appropriate solvent systemfor elution. More conveniently, the crude product may be recrystallisedfrom a suitable solvent in which the wanted ortho-nitrated product hasmore limited solubility than any contaminating nitro-isomers orby-products. The purified products may then be characterised byanalytical comparison with authentic standards (e.g. TLC) and/or theposition of nitration can be rapidly determined by NMR spectroscopy. Anadvantage of this method is that it is high yielding; the overall yieldof this nitration reaction frequently exceeding 75%. Another advantageof this method is that it is regioselective, with the regioselectivityfavouring predominant formation of the ortho-nitrated product.

For avoidance of doubt, it is stated that in formula I, R′ and R″ may besubstituted on any position on the phenyl group.

Additionally, it is envisioned that compounds represented by formula Imay be used as precursors or intermediates in the production of furtherpharmaceutically active/effective compounds. According to another aspectof the invention there is provided a method for the reparation of acompound of formula IV:

where R₄ and R₅ are the same or different and signify hydrogen,optionally substituted lower alkanoyl or aroyl, optionally substitutedlower alkoxycarbonyl, or optionally substituted lower alkylcarbamoyl; R₆signifies hydrogen or optionally substituted alkanoyl or aroyl group; R₇signifies optionally substituted saturated or partially unsaturatedlower alkyl or aryl group, or taken together with R₆ signifies anoptionally substituted saturated or partially unsaturated carbocyclicring; A signifies oxygen or NR₈ group, where R₈ signifies NHR₉ where R₉signifies optionally substituted lower alkyl or aryl group, or OR₁₀group where R₁₀ signifies hydrogen, lower alkyl or lower alkanoyl, or Asignifies an optionally substituted alkylidene when R₇ signifies OR₁₁group where R₁₁ signifies optionally substituted lower alkanoyl or aroylgroup, and pharmaceutically acceptable salts thereof; said methodcomprising the steps of: taking a compound of formula I manufactured inaccordance with the method described above, and treating said compoundto produce a compound of formula IV.

In one embodiment of these further methods, the treatment may comprise adealkylation step, which may be a demethylation step. In anotherembodiment, the treatment may comprise an acylation step. Preferably,the treatment comprises both a dealkylation step and an acylation step.

In a preferred embodiment of this method, m=1, n=1, wherein R′ is COR¹,wherein R¹ represents phenyl, and R″ is methoxy. Preferably the compoundof formula I is treated with a demethylation step and an acylation step.

In another preferred embodiment, R₄ and R₅ are both butyryl; R₆ ishydrogen; R₇ is phenyl; and A is oxygen.

The demethylation step preferably comprises reacting the compound offormula I with a methyl-acceptor in the presence of a catalyst, andcrystallizing the demethylated product. The compound of formula I may bedispersed in an organic solvent, such as ethyl acetate,1,2-dichloroethane, dichloromethane or 1,1,2,2-tetrachloroethane. Themethyl-acceptor may be pyridine and the catalyst may be aluminiumchloride. Alternatively, the methyl-acceptor and catalyst may be thesame compound, such as pyridinium chloride. The reaction may occur inthe presence of an inert gas, such as argon. Subsequently, acid, such asHCl, may be added to the reaction mixture. The addition of acid mayquench the reaction. The precipitated solid may be removed byfiltration, and is preferably washed and recrystallised.

The acylation step preferably comprises reacting the demethylatedcompound with one or more acyl-donors, such as butyric anhydride orethylchloroformate, optionally in the presence of pyridine, and acatalyst, such as 4-dimethyl-aminopyridine. The reaction may be allowedto proceed, preferably for around two hours, before the product iswashed and dried. The washing step is preferably carried out with acidand brine. The residue may be filtered and evaporated in vacuo, and thenrecrystallised, preferably from an organic solvent/petroleum ethermixture to leave the crystallized product.

A number of the moieties in formulas I, II and IV are said to be“optionally substituted”, and the methods of the invention areapplicable to a wide range of possible substitutions. Particularoptional substituents for the moieties include lower alkyl, alkoxy,halogen, nitro, amino or cyano. Thus, in this specification the term“optionally substituted” should be read, in a preferred embodiment as“optionally substituted with lower alkyl, alkoxy, halogen, nitro, aminoor cyano.”

The invention disclosed herein is exemplified by the following examplesof preparation, which should not be construed to limit the scope of thedisclosure. It is to be understood that the invention is not to belimited to the exact details of operation or structures shown, asobvious modifications and equivalents will be apparent to those skilledin the art. Examples 1–7 are examples of the nitration procedure.Example 8 is an example of a demethylation procedure. Example 9 is anexample of an acylation procedure. Alternative dealkylation andacylation procedures, reactants and quantities are readily available tothose skilled in the art (see for example the Applicant's publicationsGB2344819A, EP-A-1167341 & EP-A-1167341).

EXAMPLE 1 2-Nitrophenol

To a stirred solution of phenol (0.94 g, 10 mmol) in dichloromethane (10mL) at room temperature was added tetrabutylammoniumhydrogen sulphate(0.17 g, 5 mol %) followed by isopropyl nitrate (2.63 g, 25 mmol).Sulphuric acid (96%, 0.94 mL) was then added dropwise and the mixturebecame darker in appearance as the reaction temperature increasedgently. After five minutes, the reaction mixture was poured onto water(30 mL) and the phases were separated. The organic phase was washed withbrine and dried over anhydrous sodium sulphate. Filtration andevaporation (40° C., water aspirator pressure) afforded a dark oil whichwas chromatographed over silica gel using a petroleum ether/ethylacetate (4:1-3:1-2:1) solvent mixture for gradient elution. Thefaster-running component was isolated in pure form from the column asyellow-orange crystals (0.9 g, 65%) of m.p. 45–46° C. and which wasidentified by NMR spectroscopy as the ortho-nitrated title product,2-nitrophenol (lit. m.p. 44–45° C., Merck Index No. 6541). Theslower-running component thereafter recovered from the column wasrecrystallised from a dichloromethane/petroleum ether mixture to givepale red crystals (0.22 g, 16%) of m.p. 112–113° C. which was identifiedby NMR spectroscopy as the para-nitrated product, 4-nitrophenol (lit.m.p. 113–114° C., Merck Index No. 6542). (81% combined yield, Ortho:Paraselectivity, 4:1).

EXAMPLE 2 3-Hydroxy4-methoxy-2-nitrobenzaldehyde

To a stirred suspension of 3-hydroxy4-methoxybenzaldehyde (isovanillin,0.76 g, 5 mmol) in dichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.76 mL) wasthen added dropwise to the mixture which was allowed to stir at roomtemperature for thirty minutes and then poured onto water (50 mL). Thephases were separated and the organic layer was washed with brine anddried over anhydrous sodium sulphate. Filtration and evaporation of thesolvent (40° C., water aspirator pressure) afforded a solid residuewhich was recrystallised from a dichloromethane/petroleum ether mixtureto give orange crystals (0.74 g, 75%) of m.p. 139–140° C., identified byNMR as the ortho-nitrated title product. After concentration of themother liquors, there was obtained a small quantity of dark orangecrystals (0.11 g, 11%), corresponding (TLC) to a standard of thepara-nitrated product, 3-hydroxy4-methoxy-6-nitrobenzaldehyde. (86%combined yield, Ortho:Para selectivity, 6.8:1)

EXAMPLE 3 3-Hydroxy-4-methoxy-2-nitrobenzophenone

To a stirred solution of 3-hydroxy-4-methoxybenzophenone (10.0 g, 43.8mmol) in dichloromethane (100 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.74 g, 5 mol %) followed byisopropyl nitrate (11.5 g, 87.6 mmol). Sulphuric acid (96%, 10 mL) wasthen added dropwise causing a gently exothermic reaction, and, afterstirring for forty minutes, the reaction mixture was poured onto water(300 mL). The phases were separated and the aqueous phase was extractedby dichloromethane (30 mL). The combined organic phases were washed withbrine and dried over anhydrous sodium sulphate. Filtration andevaporation of the solvent (40° C., water aspirator pressure) afforded asolid residue which was recrystallised from a small volume of ethanol(96%, 10 mL) to afford yellow crystals, (7.97 g, 67%) of m.p. 137–139°C., identified by NMR as the ortho-nitrated title product. Concentrationof the mother liquors and subsequent chromatography on silica gel usinga petroleum ether:ethyl acetate solvent mixture (2:1) allowed theisolation of a small amount of a minor product, corresponding (TLC) to astandard of the para-nitrated product,3-hydroxy4-methoxy-6-nitrobenzophenone (1.43 g, 12%), m.p. 154–156° C.(79% combined yield, Ortho:Para selectivity, 5.6:1)

EXAMPLE 4 1-(3-Hydroxy-4-methoxy-2-nitrophenyl)-2-phenyl-ethanone

To a stirred solution of 1-(3-hydroxy4-methoxyphenyl-2-phenyl-ethanone(8.57 g, 35.4 mmol) in dichloromethane (90 mL) at room temperature wasadded tetrabutylammonium sulphate (0.6 g, 5 mol %) followed by isopropylnitrate (7.44 g, 70.8 mmol). Sulphuric acid (96%, 8.5 mL) was then addeddropwise causing a gently exothermic reaction, and after stirring forforty minutes, the reaction mixture was poured onto water (250 mL). Thephases were separated and the aqueous phase was extracted bydichloromethane (30 mL). The combined organic phases were washed withbrine and dried over anhydrous sodium sulphate. Filtration andevaporation of the solvent (40° C., water aspirator pressure) afforded asolid residue which was triturated with a small volume of diethylether(20 mL) to afford orange crystals, (6.9 g, 68%) of m.p. 176–177° C.,identified by NMR as the ortho-nitrated title product. Concentration ofthe mother liquors and subsequent trituration with diethyl ether (15 mL)allowed the isolation of a small amount of a minor product, which wasrecrystallised from a dichloromethane/heptane mixture to give yellowishcrystals of m.p. 142–143° C., corresponding (TLC) to a standard of thepara-nitrated product,1-(3-hydroxy-4-methoxy-6-nitrophenyl)-2-phenyl-ethanone (1.22 g, 12%).(80% combined yield, Ortho:Para selectivity, 5.7:1)

EXAMPLE 5 2-Hydroxy-3-nitrobenzoic acid (3-Nitrosalicylic acid)

To a stirred suspension of salicylic acid (0.69 g, 5 mmol) indichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.69 mL) wasthen added dropwise to the mixture which was allowed to stir at roomtemperature for thirty minutes (became a yellow solution, followed byformation of a yellow precipitate) and then poured onto water (50 mL).The yellow precipitate was filtered off and then triturated with water(10 mL). The insoluble material was filtered off and dried to affordyellow crystals, (0.42 g, 46%) of m.p. 121–122° C. identified by NMR asthe title compound (lit. m.p. 123° C., Merck Index No. 6553). The motherliqours were concentrated on a rotary evaporator (60° C., wateraspirator pressure) and recrystallised from a dichloromethane/petroleumether mixture to give yellow/orange crystals (0.35 g, 39%) of m.p.226–228° C., identified by NMR as 2-hydroxy-5-nitrobenzoic acid(5-nitrosalicylic acid) (lit. m.p. 228–230° C., Merck Index No. 6554).(85% combined yield, Ortho:Para selectivity, 1.2:1)

EXAMPLE 6 3-Hydroxy-2-nitrobenzaldehyde and 3-hydroxy4-nitrobenzaldehyde

To a stirred suspension of 3-hydroxybenzaldehyde (0.61 g, 5 mmol) indichloromethane (10 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol%) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.61 mL) wasthen added dropwise to the mixture causing a gentle rise in temperature.The reaction mixture was then stirred for fifteen minutes (became a darkbrown suspension) and then poured onto water (50 mL). The phases wereseparated and the aqueous phase was extracted by dichloromethane (10mL). The combined organic layers were washed by brine, dried overanhydrous sodium sulphate and filtered. Evaporation of the solvent (40°C., water aspirator pressure) afforded a brown solid which was thenchromatographed over silica gel using a petroleum ether/ethyl acetatesolvent mixture (2:1). The faster-running component was obtained fromthe column as a yellow solid (0.19 g, 23%), identified by NMR as3-hydroxy-4-nitrobenzaldehyde. The slower-running component was alsoisolated as a yellow solid, identified by NMR as3-hydroxy-2-nitrobenzaldehyde (0.56 g, 67%). (90% combined yield, bothproducts are ortho-nitrated, no para-nitro isomer was detected).

EXAMPLE 7 2,4-Difluoro-6-nitrophenol

To a stirred solution of 2,4-difluorophenol (0.65 g, 5 mmol) indichloromethane (7 mL) at room temperature was addedtetrabutylammoniumhydrogen sulphate (0.085 g, 5 mol %) followed byisopropyl nitrate (1.31 g, 12.5 mmol). Sulphuric acid (96%, 0.65 mL) wasthen added dropwise to the mixture causing gentle reflux of the solvent.The reaction mixture was then stirred for fifteen minutes and thenpoured onto water (50 mL). The phases were separated and the aqueousphase was extracted by dichloromethane (10 mL). The combined organiclayers were washed by brine, dried over anhydrous sodium sulphate andfiltered through a short pad of silica gel. Evaporation of the solvent(40° C., water aspirator pressure) afforded a yellow solid, identifiedby NMR as the title compound (0.73 g, 83%). (ortho-selectivity 100%, nonitro-isomers detected).

EXAMPLE 8 3,4-dihydroxy-2-nitrobenzophenone

To a stirred suspension of 3-Hydroxy4-methoxy-2-nitrobenzophenone (8.3g, 30.38 mmol) in 1,2-dichloroethane (100 ml) at room temperature underargon was added aluminium chloride (4.46 g, 33.45 mmol) in one portionfollowed by pyridine (9.61 g, 9.81 ml, 121.5 mmol) giving rise to anexothermic reaction. the mixture was stirred at reflux for one hour,allowed to cool to room temperature and then poured onto ice-water (300ml). Hydrochloric acid (2N, 70 ml) was added and the mixture was stirredfor one hour (initial orange precipitate gradually became yellow inappearance. The solid was removed by filtration, washed by water (30 ml)and dried under vacuum to give the product as a yellow solid 6.99 g,(89%) of melting point 153–155° C. The organic phase of the filtrate wasseparated and the aqueous phase was extracted by dichloromethane (20ml). The combined organic phases were washed by brine (30 ml), driedover anhydrous sodium sulphate and the solvent removed on a rotaryevaporator (bath temp. 40° C.) to leave a yellow solid (0.7 g) which wasnot purified further.

EXAMPLE 9 butyric acid, 3-benzoyl-6-butyrloxy-2-nitro-phenylester[3,4-dibutyryloxy-2-nitrobenzophenone]

To a stirred solution of (3,4-dihydroxy-2-nitro-phenyl)-phenyl-methanone(0.34 g, 1.29 mmol) (5 mL) [3,4-dihydroxy-2-nitrobenzophenone indichloromethane] at room temperature was added pyridine (0.41 g, 5.19mmol), butyric anhydride (0.82 g, 5.19 mmol) and4-dimethyl-aminopyridine (0.01 g). The resulting solution was stirredfor one hour and then extracted by cold water, 1N HCl and brine, thendried over sodium sulphate. After filtration and evaporation in vacuothe residue was chromatographed over silica gel using an ethylacetate/petroleum ether mixture to give off-white crystals of m.p 55 to57° C.

It will be appreciated that the invention described above may bemodified.

1. A method for the preparation of compounds of formula I

wherein: the terms R′ and R″ may be the same or different and represent:hydrogen; lower alkyl; hydroxy; lower alkoxy; halogen; the group —CO—R¹,wherein R¹ signifies hydrogen, hydroxy, alkylaryl, alkylheterocycloalkylor optionally substituted saturated or partially unsaturated lower alkylor aryl group, or R¹ signifies the group —O—R², wherein R² signifies alower alkyl or aryl group; the group —C═N—R^(a), wherein R^(a) signifiesNHR^(a), wherein R^(a) represents optionally substituted lower alkyl oraryl group, or OR^(b) group, where R^(b) signifies hydrogen, lower alkylor lower alkanoyl; the group —C—R^(c)R^(d), where R^(c) signifies anoptionally substituted alkylidene, where R^(d) represents OR^(e) groupwhere R^(e) signifies optionally substituted lower alkanoyl or arylgroup; or R′ and R″ taken together signify an optionally substitutedsaturated or partially unsaturated carbocyclic ring; m and n areindependently 0, 1 or 2; the term lower alkyl means a carbon chain,straight or branched, containing from one to six carbon atoms; the termhalogen means fluorine, chlorine, bromine or iodine; the termheterocycloalkyl means a five or six-membered cyclic ring incorporatingone or two atoms of oxygen, sulphur or nitrogen; the term aryl means aphenyl or naphthyl group optionally substituted by alkoxy, halo or nitrogroups; said method comprising reacting a phenolic compound of formulaII:

wherein the terms R′ and R″, m and n are defined above, with an alkylnitrate of formula IIIR³—ONO₂  FORMULA III where R³ represents an alkyl group straight orbranched, containing from one to sixteen carbon atoms, or R³ representsa cycloalkyl group containing either five or six carbon atoms, saidreaction of the phenolic compound of formula II with the alkyl nitrateof formula III being carried out in the presence of an acid catalyst. 2.The method according to claim 1, wherein the acid catalyst is a mineralacid or an organic acid.
 3. The method according to claim 1, wherein theacid catalyst is sulphuric acid.
 4. The method according to claim 1,wherein the acid catalyst is a Lewis acid catalyst.
 5. The methodaccording to claim 1 wherein the alkyl nitrate is isopropyl nitrate. 6.The method according to claim 1 wherein the alkyl nitrate is isobutylnitrate.
 7. The method according to claim 1 wherein the alkyl nitrate isisoamyl nitrate (isopentyl nitrate).
 8. The method according to claim 1wherein the alkyl nitrate is isooctyl nitrate (2-ethylhexyl nitrate). 9.The method according to claim 1 wherein the phenolic compound is3-hydroxy4-methoxybenzophenone.
 10. The method according to claim 1,wherein R′ and R″ may be the same or different and signify saturated orpartially unsaturated lower alkyl or aryl group, optionally substitutedwith lower alkyl, alkoxy, halogen, nitro, amino or cyano.
 11. A methodaccording to claim 1, for preparing a compound of formula IV:

where R₄ and R₅ are the same or different and signify hydrogen,optionally substituted lower alkanoyl or aroyl, optionally substitutedlower alkoxycarbonyl, or optionally substituted lower alkylcarbamoyl; R₆signifies hydrogen or optionally substituted alkanoyl or aroyl group; R₇signifies optionally substituted saturated or partially unsaturatedlower alkyl or aryl group, or taken together with R₆ signifies anoptionally substituted saturated or partially unsaturated carbocyclicring; A signifies oxygen or NR₈ group, where R₈ signifies NHR₉ where R₉signifies optionally substituted lower alkyl or aryl group, or OR₁₀group where R₁₀ signifies hydrogen, lower alkyl or lower alkanoyl, or Asignifies an optionally substituted alkylidene when R₇ signifies OR₁₁,group where R₁₁ signifies optionally substituted lower alkanoyl or aroylgroup, and pharmaceutically acceptable salts thereof; wherein saidmethod comprises the step of: taking a compound of formula I, andtreating said compound to produce a compound of formula IV.
 12. Themethod according to claim 11, wherein the phenolic compound of formulaII is 3-hydroxy4-methoxybenzophenone, and the intermediate compound offormula I is 3-hydroxy4-methoxy-2-nitrobenzophenone.
 13. The methodaccording to claim 11, wherein the compound of formula IV is butyricacid, 3-benzoyl-6-butyryloxy-2-nitrophenyl ester.
 14. The methodaccording to claim 11, wherein the treatment comprises a dealkylationstep.
 15. The method according to claim 11, wherein the dealkylationstep comprises a demethylation step.
 16. The method according to claim15, wherein the demethylation step comprises reacting the compound offormula I with a methyl acceptor, in the presence of a catalyst, andrecrystallizing the demethylated product.
 17. The method according toclaim 11, wherein the treatment comprises an acylation step.
 18. Themethod according to claim 17, wherein the acylation step comprisesreacting the compound of formula I, or its demethylated equivalent withan acyl-donor in the presence of a catalyst.
 19. The method according toclaim 11, wherein m=1, n=1, R′ is —COR¹, wherein R¹ represents phenyl,and R″ is a methoxy group; the treatment comprising a demethylation stepand an acylation step.
 20. The method according to claim 19, wherein R₄and R₅ are both butyryl; R₆ is hydrogen; R₇ is phenyl; and A is oxygen.21. The method according to claim 15, wherein the demethylation stepcomprises reacting the compound of formula I with a methyl acceptor, inthe presence of a catalyst selected from the group consisting ofaluminum chloride and pyridinium chloride, and recrystallizing thedemethylated product.
 22. The method according to claim 17, wherein theacylation step comprises reacting the compound of formula I, or itsdemethylated equivalent with an acyl-donor in the presence of a4-dimethyl-aminopyridine catalyst.